Platelet-activating factor (PAF, 1-0-alkyl-2-acetyl-sn-glycerol-3-phosphorylcholine) is a potent inflammatory phospholipid mediator that binds to and activates platelet-activating factor receptor (PAFR). PAF is produced and released by monocytes, macrophages, polymorphonuclear leukocytes (PMNs), eosinophils, neutrophils, natural killer lymphocytes, platelets and endothelial cells, as well as by renal and cardiac tissues under appropriate immunological and non-immunological stimulation. PAF is similar to other lipid mediators such as thromboxane A, prostaglandins, and leukotrienes with respect to the level of potency (active at 10−12 to 10−9M), tissue amount (picomoles) and short plasma half life (2-4 minutes). PAF is physiologically active and causes contraction of the airway smooth muscle, increased vascular permeability, platelet aggregation, and hypotension. Reviewed in: Prescott, S. M. et al. Annu. Rev. Biochem. 2000, 69, 419-445; Honda et al. J. Biochem. 2002, 131, 773-779; Stafforini et al. Crit. Rev. Clin. Lab Sci. 2003, 40, 643-672.
PAF has been reported to participate in several aspects of the inflammatory response associated with the pathogenesis of atheroscloerosis, however, the precise role of PAF/PAFR has not been defined. PAF activates the adhesive interaction of leukocytes with the vascular endothelium and the transmigration of leukocytes, promotes the release of reactive oxygen species and tissue-damaging enzymes from leukocytes and endothelial cells, induces the synthesis of inflammatory cytokines from monocytes, and causes the aggregation and degranulation of platelets. In addition, PAF receptor has been shown to recognize both PAF and PAF-like oxidized phospholipids on LDL and may promote an inflammatory response to them (Frostegard, J. et al., Arterioscler. Thromb. Vasc. Biol. 1997, 17, 963-968; Leitinger, N. Curr. Opin. Lipidol. 2003, 14, 421-430). A PAFR antagonist was reported to reduce atherosclerotic lesion area by 62% in Ldlr−/− mice fed an atherogenic diet (Subbanagounder, G. et al., Circ. Res. 1999, 85, 311-318). PAF may also promote smooth muscle cell proliferation, angiogenesis and elastase release. These activities have the potential to contribute to lesion formation or to the generation of occlusive thrombi at the site of plaque rupture (Reviewed in: Demopoulos, C. A. et al., Eur. J. Lipid Sci. Technol. 2003, 105, 705-716; Zimmerman, G. A. et al. Crit. Care Med. 2002, 30, S294-S301).
PAF has also been implicated in both peripheral and neuropathic pain responses. PAF can induce hyperalgesia when injected subcutaneously into a rat paw (Bonnet, J. et al., INSERM 1981, 100, 111; Vargaftig, B. B.; Ferreira, S. H. Braz. J. Med. Biol. Res. 1981, 14, 187) and PAFR antagonists were reported to decrease the inflammatory nociceptive response in rats (Mather, L. A. Psychopharmacology 2002, 163, 430-433). PAF may also mediate neuropathic pain responses. Intrathecal administration of PAF in mice caused the development of tactile allodynia and thermal hyperalgesia (Morita, K. et al., Pain 2004, 111, 351-359). PAF is expressed in the spinal cord and DRG neurons. A PAFR agonist evoked an intracellular Ca2+ flux in capsaicin-sensitive DRG but not in Pafr−/− mice, and it has been proposed that PAF may function in both persistent pain and the sensitization of primary sensory neurons after tissue injury (Tsuda, M. et al., J. Neurochem. 2007, 102, 1658-1668).
PAF also appears to play a role in pathological allergic, hypersecretory and additional inflammatory responses. Many published studies suggest the involvement of PAF in autoimmune and inflammatory human diseases, including anaphylaxis, rheumatoid arthritis, acute inflammation, asthma, endotoxic shock, ischemia, gastrointestinal ulceration, transplanted organ rejection, reperfusion injury, inflammatory bowel diseases, edema, rhinitis, thrombosis, bronchitis, urticaria, psoriasis, retinal and corneal diseases, chemically induced liver cirrhosis, and ovimplantation in pregnancy, and acute respiratory distress syndrome. References include: Piper, P. J. et al., Ann. NY Acad. Sci. 1991, 629, 112-119; Holtzman, M. J. Am. Rev. Respir. Dis. 1991, 143, 188-203; Snyder, F. Am. J. Physiol. Cell Physiol. 1990, 259, C697-C708; Prescott, S. M. et al., J. Biol. Chem. 1990, 265, 17381-17384; (cardiac diseases) Feuerstein, G. et al., J Lipid Mediat. Cell Signal. 1997, 15, 255-284; (liver injury) Karidis, N. P. et al., World J. Gastroenterol. 2006, 12, 3695-3706; (pancreatitis) Liu, L. R.; Xia, S. H. World J. Gastroenterol. 2006, 12, 539-545; (lung) Uhlig, S. et al., Pharamcol. Rep. 2005, 57, 206-221; (thrombosis) Prescott, S. M. et al., Arterioscler. Thromb. Vasc. Biol. 2002, 22, 727-733; Ishii, S.; Shimizu, T. Prog. Lipid Res. 2000, 39, 41-82. Compounds and/or pharmaceutical compositions which act as PAF receptor antagonists should be of value in the treatment of any of the above conditions.
Despite significant therapeutic advances in the treatment and prevention of atherosclerosis and ensuing atherosclerotic disease events, such as the improvements that have been achieved with HMG-CoA reductase inhibitors, further treatment options are clearly needed. Moreover, there is a need for additional treatment options, in addition to the therapeutics that exist, for the treatment of both inflammatory and neuropathic pain. The instant invention addresses those needs by providing compounds, compositions and methods for the treatment or prevention of atherosclerosis and pain as well as related and other immune conditions.